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nmdar inhibition

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https://www.readbyqxmd.com/read/29793154/juvenile-treatment-with-mglur2-3-agonist-prevents-schizophrenia-like-phenotypes-in-adult-by-acting-through-gsk3%C3%AE
#1
Bo Xing, Genie Han, Min-Juan Wang, Melissa A Snyder, Wen-Jun Gao
Prodromal memory deficits represent an important marker for the development of schizophrenia (SZ), in which glutamatergic hypofunction occurs in the prefrontal cortex (PFC). The mGluR2/3 agonist LY379268 (LY37) attenuates excitatory N-methyl-D-aspartate receptor (NMDAR)-induced neurotoxicity, a central pathological characteristic of glutamatergic hypofunction. We therefore hypothesized that early treatment with LY37 would rescue cognitive deficits and confer benefits for SZ-like behaviors in adults. To test this, we assessed whether early intervention with LY37 would improve learning outcomes in the Morris Water Maze for rats prenatally exposed to methylazoxymethanol acetate (MAM), a neurodevelopmental SZ model...
May 14, 2018: Neuropharmacology
https://www.readbyqxmd.com/read/29793153/effects-of-mg-2-on-recovery-of-nmda-receptors-from-inhibition-by-memantine-and-ketamine-reveal-properties-of-a-second-site
#2
Nathan G Glasgow, Madeleine R Wilcox, Jon W Johnson
Memantine and ketamine are NMDA receptor (NMDAR) open channel blockers that are thought to act via similar mechanisms at NMDARs, but exhibit divergent clinical effects. Both drugs act by entering open NMDARs and binding at a site deep within the ion channel (the deep site) at which the endogenous NMDAR channel blocker Mg2+ also binds. Under physiological conditions, Mg2+ increases the IC50 s of memantine and ketamine through competition for binding at the deep site. Memantine also can inhibit NMDARs after associating with a second site accessible in the absence of agonist, a process termed second site inhibition (SSI) that is not observed with ketamine...
May 12, 2018: Neuropharmacology
https://www.readbyqxmd.com/read/29792594/an-nmdar-positive-and-negative-allosteric-modulator-series-share-a-binding-site-and-are-interconverted-by-methyl-groups
#3
Riley Perszyk, Brooke M Katzman, Hirofumi Kusumoto, Steven A Kell, Matthew P Epplin, Yesim A Tahirovic, Rhonda L Moore, David Menaldino, Pieter Burger, Dennis C Liotta, Stephen F Traynelis
N-methyl-d-aspartate receptors (NMDARs) are an important receptor in the brain and have been implicated in multiple neurological disorders. Many non-selective NMDAR-targeting drugs are poorly tolerated, leading to efforts to target NMDAR subtypes to improve the therapeutic index. We describe here a series of negative allosteric NMDAR modulators with submaximal inhibition at saturating concentrations. Modest changes to the chemical structure interconvert negative and positive modulation. All modulators share the ability to enhance agonist potency and are use-dependent, requiring the binding of both agonists before modulators act with high potency...
May 24, 2018: ELife
https://www.readbyqxmd.com/read/29791859/combining-ngn2-programming-with-developmental-patterning-generates-human-excitatory-neurons-with-nmdar-mediated-synaptic-transmission
#4
Ralda Nehme, Emanuela Zuccaro, Sulagna Dia Ghosh, Chenchen Li, John L Sherwood, Olli Pietilainen, Lindy E Barrett, Francesco Limone, Kathleen A Worringer, Sravya Kommineni, Ying Zang, Davide Cacchiarelli, Alex Meissner, Rolf Adolfsson, Stephen Haggarty, Jon Madison, Matthias Muller, Paola Arlotta, Zhanyan Fu, Guoping Feng, Kevin Eggan
Transcription factor programming of pluripotent stem cells (PSCs) has emerged as an approach to generate human neurons for disease modeling. However, programming schemes produce a variety of cell types, and those neurons that are made often retain an immature phenotype, which limits their utility in modeling neuronal processes, including synaptic transmission. We report that combining NGN2 programming with SMAD and WNT inhibition generates human patterned induced neurons (hpiNs). Single-cell analyses showed that hpiN cultures contained cells along a developmental continuum, ranging from poorly differentiated neuronal progenitors to well-differentiated, excitatory glutamatergic neurons...
May 22, 2018: Cell Reports
https://www.readbyqxmd.com/read/29772491/calpain-inhibition-reduces-nmda-receptor-rundown-in-rat-substantia-nigra-dopamine-neurons
#5
Jerry Zhao, Michel Baudry, Susan Jones
Repeated activation of N-Methyl-d-aspartate receptors (NMDARs) causes a Ca2+ -dependent reduction in NMDAR-mediated current in dopamine (DA) neurons of the substantia nigra pars compacta (SNc) in one week old rats; however, a Ca2+ -dependent regulatory protein has not been identified. The role of the Ca2+ -dependent cysteine protease, calpain, in mediating NMDAR current rundown was investigated. In brain slices from rats aged postnatal day 7-9 ('P7'), bath application of either of the membrane permeable calpain inhibitors, N-Acetyl-L-leucyl-L-leucyl-L-norleucinal (ALLN, 20 μM) or MDL-28170 (30 μM) significantly reduced whole-cell NMDAR current rundown...
May 4, 2018: Neuropharmacology
https://www.readbyqxmd.com/read/29767953/pharmacological-and-electrophysiological-characterization-of-novel-nmda-receptor-antagonists
#6
Rosana Leiva, Matthew B Phillips, Andreea Larisa Turcu, Esther Gratacòs-Batlle, Lara León-García, Francesc X Sureda, David Soto, Jon W Johnson, Santiago Vazquez
This work reports the synthesis, and pharmacological and electrophysiological evaluation of new N-methyl-D-aspartic acid receptor (NMDAR) channel blocking antagonists featuring polycyclic scaffolds. Changes in the chemical structure modulate the potency and voltage dependence of inhibition. Two of the new antagonists display properties comparable to those of memantine, a clinically approved NMDAR antagonist.
May 16, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29766040/the-midline-axon-crossing-decision-is-regulated-through-an-activity-dependent-mechanism-by-the-nmda-receptor
#7
Jingxia Gao, Tamara J Stevenson, Adam D Douglass, Joshua P Barrios, Joshua L Bonkowsky
Axon guidance in vertebrates is controlled by genetic cascades as well as by intrinsic activity-dependent refinement of connections. Midline axon crossing is one of the best studied pathfinding models and is fundamental to the establishment of bilaterally symmetric nervous systems. However, it is not known whether crossing requires intrinsic activity in axons, and what controls that activity. Further, a mechanism linking neuronal activity and gene expression has not been identified for axon pathfinding. Using embryonic zebrafish, we found that the NMDA receptor (NMDAR) NR1...
March 2018: ENeuro
https://www.readbyqxmd.com/read/29749407/peripheral-n-methyl-d-aspartate-receptor-localization-and-role-in-gastric-acid-secretion-regulation-immunofluorescence-and-pharmacological-studies
#8
Iuliia Golovynska, Tatiana V Beregova, Tatiana M Falalyeyeva, Ludmila I Stepanova, Sergii Golovynskyi, Junle Qu, Tymish Y Ohulchanskyy
The enteric nervous system (ENS) and a glutamate receptor (GluR), N-methyl-D-aspartate receptor (NMDAR), participate in gastric acid secretion (GAS) regulation. NMDARs are localized in different stomach cells; however, knowledge of NMDAR expression and function in the ENS is limited. In the present study, we clarified the types of stomach cells that express the NMDARs that are involved in GAS regulation. The pharmacological method of isolated stomach perfusion by Ghosh and Shild combined with direct mapping of NMDARs by fluorescence microscopy in the rat stomach was employed...
May 10, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29740596/neuregulin-1-type-i-overexpression-is-associated-with-reduced-nmda-receptor-mediated-synaptic-signaling-in-hippocampal-interneurons-expressing-pv-or-cck
#9
Dimitrios Kotzadimitriou, Wiebke Nissen, Melinda Paizs, Kathryn Newton, Paul J Harrison, Ole Paulsen, Karri Lamsa
Hypofunction of N -methyl-d-aspartate receptors (NMDARs) in inhibitory GABAergic interneurons is implicated in the pathophysiology of schizophrenia (SZ), a heritable disorder with many susceptibility genes. However, it is still unclear how SZ risk genes interfere with NMDAR-mediated synaptic transmission in diverse inhibitory interneuron populations. One putative risk gene is neuregulin 1 ( NRG1 ), which signals via the receptor tyrosine kinase ErbB4, itself a schizophrenia risk gene. The type I isoform of NRG1 shows increased expression in the brain of SZ patients, and ErbB4 is enriched in GABAergic interneurons expressing parvalbumin (PV) or cholecystokinin (CCK)...
March 2018: ENeuro
https://www.readbyqxmd.com/read/29736613/inhibition-of-acid-sensing-ion-channel-3-aggravates-seizures-by-regulating-nmdar-function
#10
Qian Cao, Zhe-Man Xiao, Xi Wang, Chao Weng, Man Ding, Fan Zhu, Zu-Neng Lu
The existing data about whether acid sensing ion channels (ASICs) are proconvulsant or anticonvulsant are controversial. Particularly, acid sensing ion channel 3 (ASIC3) is the most sensitive to extracellular pH and has the characteristic ability to generate a biphasic current, but few studies have focused on the role of ASIC3 in seizure. Here we found ASIC3 expression was increased in the hippocampus of pilocarpine induced seizure rats, as well as in hippocampal neuronal cultures undergoing epileptiform discharge elicited by Mg2+ -free media...
May 7, 2018: Neurochemical Research
https://www.readbyqxmd.com/read/29729989/sustained-activation-of-jnk-induced-by-quinolinic-acid-alters-the-bdnf-trkb-axis-in-the-rat-striatum
#11
Ricardo A Santana-Martínez, Juan Carlos León-Contreras, Diana Barrera-Oviedo, José Pedraza-Chaverri, Rogelio Hernández-Pando, Perla D Maldonado
Oxidative stress secondary to excitotoxicity is a common factor in the physiopathology of a variety of neurological disorders. In response to oxidative stress, several signaling pathways, such as MAPK, are activated or inactivated. MAPK family activation must be finely regulated in time and intensity, as this pathway may either preserve cell survival or promote cell death. In the present study, the activation of MAPK in the excitotoxic injury induced by quinolinic acid (QUIN) was examined in vivo, at short and long times...
May 3, 2018: Neuroscience
https://www.readbyqxmd.com/read/29723576/beta-and-gamma-oscillations-in-prefrontal-cortex-during-nmda-hypofunction-an-in-vitro-model-of-schizophrenia-features
#12
Beatriz Rebollo, Maria Perez-Zabalza, Marcel Ruiz-Mejias, Lorena Perez-Mendez, Maria V Sanchez-Vives
NMDA receptor (NMDAr) hypofunction has been widely used as a schizophrenia model. Decreased activation of NMDAr is associated with a disrupted excitation/inhibition balance in the prefrontal cortex and with alterations in gamma synchronization. Our aim was to investigate whether this phenomenon could be reproduced in the spontaneous oscillatory activity generated by the local prefrontal network in vitro and, if so, to explore the effects of antipsychotics on the resulting activity. Extracellular recordings were obtained from prefrontal cortex slices bathed in in vivo-like ACSF solution...
April 30, 2018: Neuroscience
https://www.readbyqxmd.com/read/29722562/nmda-receptor-activation-inhibits-the-anti-fibrotic-effect-of-bm-mscs-on-bleomycin-induced-pulmonary-fibrosis
#13
Xiao-Hong Li, Chen Li, Yiting Tang, Yan-Hong Huang, Qing-Mei Cheng, Xiao-Ting Huang, Feiyan Zhao, Cai-Xia Hao, Dan-Dan Feng, Jian-Ping Xu, Jianzhong Han, Siyuan Tang, Wei Liu, Shaojie Yue, Zi-Qiang Luo
Endogenous glutamate (Glu) release and N-methyl-D-aspartate (NMDA) receptor (NMDAR) activation are associated with lung injury in different animal models. However, the underlying mechanism is unclear. Bone marrow-derived mesenchymal stem cells (BM-MSCs), which show potential use for immunomodulation and tissue-protection, play a protective role in pulmonary fibrosis (PF) process. Here, we found the increased Glu release from the BM cells of bleomycin (BLM)-induced PF mice in vivo. BLM stimulation also increased the extracellular Glu in BM-MSCs via the antiporter system xc- in vitro...
May 3, 2018: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/29708744/positive-modulators-of-the-n-methyl-d-aspartate-receptor-structure-activity-relationship-study-on-steroidal-3-hemiesters
#14
Barbora Krausova, Barbora Slavikova, Michaela Nekardova, Pavla Hubalkova, Vojtech Vyklicky, Hana Chodounska, Ladislav Vyklicky, Eva Kudova
Here, we report the synthesis of pregn-5-ene and androst-5-ene dicarboxylic acid esters and explore the structure-activity relationship (SAR) for their modulation of N-methyl- D-aspartate receptors (NMDARs). All compounds were positive modulators of recombinant GluN1/GluN2B receptors (EC50 varying from 1.8 to 151.4 µM and Emax varying from 48 to 452 %). Moreover, 10 compounds were found to be more potent GluN1/GluN2B receptor modulators than endogenous pregnenolone sulfate (EC50 = 21.7 µM). The SAR study revealed a relationship between the length of the residues at carbon C-3 of the steroid molecule and the positive modulatory effect at GluN1/GluN2B receptors for various D-ring modifications...
April 30, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29704481/grewia-tiliaefolia-and-its-active-compound-vitexin-regulate-the-expression-of-glutamate-transporters-and-protect-neuro2a-cells-from-glutamate-toxicity
#15
Dicson Sheeja Malar, Mani Iyer Prasanth, Rajamohamed Beema Shafreen, Krishnaswamy Balamurugan, Kasi Pandima Devi
AIM: Glutamate is a major neurotransmitter involved in several brain functions and glutamate excitotoxicity is involved in Alzheimer's disease (AD). In the current study, the neuroprotective effect of the Indian medicinal plant Grewia tiliaefolia (GT) and its active component vitexin was evaluated in Neuro-2a cells against glutamate toxicity. MATERIALS AND METHODS: Neuro-2a cells were exposed to glutamate to cause excitotoxicity and the neuroprotective effect of GT and vitexin were evaluated using biochemical studies (estimation of reactive oxygen species, reactive nitrogen species, protein carbonyl content, lipid peroxidation level, mitochondrial membrane potential and caspase-3 activity), molecular docking studies, gene expression and western blot analysis...
April 25, 2018: Life Sciences
https://www.readbyqxmd.com/read/29700292/enhancement-of-5-ht-2a-receptor-function-and-blockade-of-kv1-5-by-mk801-and-ketamine-implications-for-pcp-derivative-induced-disease-models
#16
Haiyue Lin, Jae Gon Kim, Sang Woong Park, Hyun Ju Noh, Jeong Min Kim, Chang Yong Yoon, Nam-Sik Woo, Bokyung Kim, Sung Il Cho, Bok Hee Choi, Dong Jun Sung, Young Min Bae
MK801 and ketamine, which are phencyclidine (PCP) derivative N-methyl-d-aspartate receptor (NMDAr) blockers, reportedly enhance the function of 5-hydroxytryptamine (HT)-2A receptors (5-HT2A Rs). Both are believed to directly affect the pathogenesis of schizophrenia, as well as hypertension. 5-HT2A R signaling involves the inhibition of Kv conductance. This study investigated the interaction of these drugs with Kv1.5, which plays important roles in 5-HT2A R signaling and in regulating the excitability of the cardiovascular and nervous system, and the potential role of this interaction in the enhancement of the 5-HT2A R-mediated response...
April 27, 2018: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/29695962/inhibition-of-nmda-receptors-prevents-the-loss-of-bdnf-function-induced-by-amyloid-%C3%AE
#17
Sara R Tanqueiro, Rita M Ramalho, Tiago M Rodrigues, Luísa V Lopes, Ana M Sebastião, Maria J Diógenes
Brain-derived neurotrophic factor (BDNF) plays important functions in cell survival and differentiation, neuronal outgrowth and plasticity. In Alzheimer's disease (AD), BDNF signaling is known to be impaired, partially because amyloid β (Aβ) induces truncation of BDNF main receptor, TrkB-full length (TrkB-FL). We have previously shown that such truncation is mediated by calpains, results in the formation of an intracellular domain (ICD) fragment and causes BDNF loss of function. Since calpains are Ca2+ -dependent proteases, we hypothesized that excessive intracellular Ca2+ build-up could be due to dysfunctional N-methyl-d-aspartate receptors (NMDARs) activation...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29695955/glyx-13-ameliorates-schizophrenia-like-phenotype-induced-by-mk-801-in-mice-role-of-hippocampal-nr2b-and-disc1
#18
Dongsheng Zhou, Dan Lv, Zhen Wang, Yanhua Zhang, Zhongming Chen, Chuang Wang
Background: Evidence supports that the hypofunction of N -methyl-D-aspartate receptor (NMDAR) and downregulation of disrupted-in-schizophrenia 1 (DISC1) contribute to the pathophysiology of schizophrenia. N -Methyl D-aspartate receptor subtype 2B (NR2B)-containing NMDAR are associated with cognitive dysfunction in schizophrenia. GLYX-13 is an NMDAR glycine-site functional partial agonist and cognitive enhancer that does not induce psychotomimetic side effects. However, it remains unclear whether NR2B plays a critical role in the GLYX-13-induced alleviation of schizophrenia-like behaviors in mice...
2018: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/29675583/do-alcohol-related-ampa-type-glutamate-receptor-adaptations-promote-intake
#19
F Woodward Hopf, Regina A Mangieri
Ionotropic glutamate receptors (AMPA, NMDA, and kainate receptors) play a central role in excitatory glutamatergic signaling throughout the brain. As a result, functional changes, especially long-lasting forms of plasticity, have the potential to profoundly alter neuronal function and the expression of adaptive and pathological behaviors. Thus, alcohol-related adaptations in ionotropic glutamate receptors are of great interest, since they could promote excessive alcohol consumption, even after long-term abstinence...
April 20, 2018: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/29628771/activation-of-spinal-dorsal-horn-p2y-13-receptors-can-promote-the-expression-of-il-1%C3%AE-and-il-6-in-rats-with-diabetic-neuropathic-pain
#20
Rui Zhou, Tao Xu, XiaoHong Liu, YuanShou Chen, DeYing Kong, Hong Tian, Mingxia Yue, Dujuan Huang, Junwei Zeng
Objective: The dorsal horn P2Y13 receptor is involved in the development of pain behavior induced by peripheral nerve injury. It is unclear whether the expression of proinflammatory cytokines interleukin (IL)-1β and IL-6 at the spinal dorsal horn are influenced after the activation of P2Y13 receptor in rats with diabetic neuropathic pain (DNP). Methods: A rat model of type 1 DNP was induced by intraperitoneal injection of streptozotocin (STZ). We examined the expression of P2Y13 receptor, Iba-1, IL-1β, IL-6, JAK2, STAT3, pTyr1336 , and pTyr1472 NR2B in rat spinal dorsal horn...
2018: Journal of Pain Research
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